Abstract
Benefits and risks were reported for hormone therapy (HT) to prevent chronic disease, including Alzheimer’s disease (AD). While the Women’s Health Initiative (WHI) found no protective effect of HT on the cognitive function of women whose treatment was initiated far past the onset of menopause, other studies showed reduced risk of AD with midlife treatment, versus increased risk of AD with late treatment. These suggest a critical window during which estradiol must be administered to prevent cognitive decline and AD in women. Our published work supports this, by demonstrating that early and long-term estradiol treatment improves cognitive function and reduce Aβ accumulation in AD mouse models with estradiol deficiency, while there is no effect of late and short-term estradiol treatment on AD neuropathogenesis. However, little is known about the molecular mechanisms underlying the critical window and whether different protein networks are responsible for the brain estradiol deficiency-associated risk of AD in females. In this study, we used proteomics to identify target protein pathways that are activated during the estradiol therapeutic window in AD mouse model. Our results showed that different signaling pathways were involved in the regulatory effects of estradiol on MAP1A and hemoglobin α. Estradiol treatment increased the level of MAP1A through the phosphorylation of ERK1/2 and increased the level of hemoglobin α through the phosphorylation of AKT. This study has provided molecular insights into the “critical window” theory and identifies specific target proteins of therapeutic responsiveness that may lead to improved treatment strategies and optimal estradiol therapy.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and most common neurodegenerative disease in the world
The critical window of hormone therapy (HT) states that the effects of HT depend on the timing of initiation of treatment with respect to age and/or the menopausal transition, and that optimal effects are evident with early initiation (Marder and Sano, 2000; Resnick and Henderson, 2002)
The critical window hypothesis of HT and cognitive function states that the effects of HT depend on the timing of initiation with respect to age and/or the menopausal transition and that optimal effects are evident with early initiation
Summary
Alzheimer’s disease (AD) is the most common form of dementia and most common neurodegenerative disease in the world. Imaging studies showed that women receiving HT at early menopause for 4 years developed less AD plaques than women who were not treated (Kantarci et al, 2016). The critical window of HT (same as the timing hypothesis or the critical period hypothesis) states that the effects of HT depend on the timing of initiation of treatment with respect to age and/or the menopausal transition, and that optimal effects are evident with early initiation (Marder and Sano, 2000; Resnick and Henderson, 2002). There have been several observational studies or clinical trials providing support for the hypothesis, such as the Women’s Health Initiative Memory Study (WHIMS) (Shumaker et al, 2003; Shumaker et al, 2004), the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) study (Henderson et al, 2005), the Cache County Study (Zandi et al, 2002), and the Kronos Early Estrogen Prevention Study (KEEPS) (Kantarci et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
